The repression of Insulin/IGF signaling (IIS) by stress signaling pathways is a central mechanism to promote stress tolerance and metabolic homeostasis in metazoans, extending lifespan. Recent studies in mouse progeria models demonstrate that DNA damage is an important stimulus for the systemic repression of IIS, and that this repression increases cytoprotective processes in insulin target tissues, serving as an adaptive mechanism. The mechanisms governing the repression of IIS by DNA damage remain unclear. The authors introduce a Drosophila model to address this question and propose that a network of endocrine signaling by inflammatory cytokines modulates IIS activity by regulating expression of insulin-like peptides in Insulin Producing Cells of the brain. This network is proposed to significantly influence tissue and metabolic homeostasis, as well as lifespan in the fly. To test this hypothesis and to explore the proposed signaling hierarchies, the authors propose genetic studies addressing the following questions: (i) Does release of inflammatory cytokines from stressed tissues repress Insulin signaling systemically by regulating Insulin-like peptide expression? (ii) Does signaling by NFkappaB-like factors regulate a secondary response that allows restoring Insulin activity after stress? (iii) Can a temporal and spatial sequence of endocrine signaling interactions that control the systemic response to DNA damage be characterized? (iv) Does the established endocrine signaling network regulate metabolic and proliferative homeostasis and longevity in aging flies? The proposed experiments are expected to provide important insight into the signaling network regulating insulin signaling in response to DNA damage and other stressful challenges in metazoans. These interactions are expected to be evolutionarily conserved and potentially influence stress tolerance and lifespan in vertebrates, while at the same time playing significant roles in promoting metabolic dysfunction under chronic inflammatory conditions, as observed in obese animals.